Biophysical and cell-based evidence for differential interactions between the death domains of CD95/Fas and FADD

Ferguson, Brian J.; Esposito, Diego; Jovanovic, Jasmina N.; Sankar, Andrew; Driscoll, Paul C.; Mehmet, Huseyin

doi:10.1038/sj.cdd.4402191

Cited by 10 publications

(16 citation statements)

References 21 publications

(10 reference statements)

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“…2b-d), which is further corroborated by previously reported results of a solubility enhanced complex which also pointed to a tetrameric arrangement27. Taken together these results establish that the observed tetramer in the crystal structure reflects the Fas/FADD DD arrangement present in solution and is not a result of crystal formation.…”

supporting

confidence: 89%

The Fas–FADD death domain complex structure unravels signalling by receptor clustering

Scott

Stec

Pop

et al. 2008

Nature

326

335

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The Death Inducing Signaling Complex (DISC) formed by Fas receptor, FADD and caspase-8 is a pivotal trigger of apoptosis1-3. The Fas/FADD DISC represents a receptor platform, which once assembled initiates the induction of programmed cell death. A highly oligomeric network of homotypic protein interactions comprised of the death domains (DD) of Fas and FADD is at the center of DISC formation4, 5. Thus characterising the mechanistic basis for the Fas/FADD interaction is paramount for understanding DISC signaling but has remained enigmatic largely due to a lack of structural data. We have successfully formed and isolated the Fas/FADD DD complex and here we report the 2.7 Å crystal structure. The complex shows a tetrameric arrangement of four FADD DDs bound to four Fas DDs. We show that an opening of the Fas DD exposes the FADD binding site and simultaneously generates a Fas/Fas bridge. The result is a regulatory Fas/FADD complex bridge governed by weak protein:protein interactions revealing a model where the complex functions as a mechanistic switch. This switch prevents accidental DISC assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. Thus besides depicting a previously unknown mode of death domain interactions, these results further uncover a mechanism for receptor signaling solely by oligomerization and clustering events.

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supporting

confidence: 89%

The Fas–FADD death domain complex structure unravels signalling by receptor clustering

Scott

Stec

Pop

et al. 2008

Nature

326

335

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“…Yet the structure of the Fas/FADD DD complex reveals an answer to this question. In the structure the complex adopts a tetrameric arrangement as confirmed by various complementary biochemical/biophysical techniques and also independently by a report using a solubility enhanced Fas/FADD DD complex,23,30 verifying the validity of the structural arrangement (Fig. 3).…”

Section: Connecting the Dots—the Mechanism Of Disc Formationsupporting

confidence: 56%

“…The Fas/FADD DD complex adopts a tetrameric arrangement of four primary Fas/FADD DD complexes in the crystal structure reflecting the oligomerisation state in solution as verified by biochemical and biophysical characterization 23,30. All contacts building the tetramer are built by Fas (square) and strictly dependent on the open form (all FADD DDs are displayed in light blue).…”

Section: Figuresmentioning

confidence: 79%

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Structure of the Fas/FADD complex: A conditional death domain complex mediating signaling by receptor clustering

Salvesen¹,

Riedl²

2009

Cell Cycle

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Death domain complexes are key protein arrangements in the regulation of various cellular signaling events. One of the most prominent death domain complexes first described in the initiation of apoptosis is formed by the transmembrane receptor Fas, the cytosolic adaptor protein FADD, and caspase-8 and is referred to as the Fas/FADD/caspase-8 death inducing signaling complex (DISC). The recent structure of the Fas/FADD death domain complex reveals how formation of this signaling platform can be stringently regulated utilizing only Fas receptor clustering to form a death domain network. This work reveals that an opening mechanism of Fas is needed to expose binding sites for the FADD death domain and sets the stage for a conditional interaction, which is characterized by weak interactions adapted for a regulatory function. The overall crystal structure reveals a tetrameric arrangement of four primary Fas/FADD complexes. Intriguingly all contacts mediating the tetramer are solely provided through Fas/Fas interactions and are entirely dependent on the open form. These findings are instrumental in depicting a mechanism for DISC regulation where Fas receptor clustering leads to the stabilization of the open Fas death domains which are then capable of binding FADD in a weak interaction. At the same time this mechanism ensures that in the absence of a sufficient stimulus no interaction between Fas and FADD is possible. Therefore the conformation dependent, conditional Fas/FADD death domain interaction represents the regulatory element per se. This interaction contrasts the classic constitutive interactions of adaptor domains, which cannot provide regulatory function themselves. This model portrays how sole death domains are able to mediate signaling upon receptor clustering in the complete absence of enzyme activity.

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“…Recent solution studies on FasDD and its interaction with FADD were conducted on a mutant (K247A) that inhibits FasDD aggregation (48). NMR data have also shown that D244A mutant inhibits FasDD self-association without altering the Fas structure (29,49). For initial characterization of its binding to CaM, we have made a protein construct of wild type FasDD encompassing residues 205-305 (Fas wt ).…”

Section: Mutants Inhibit Fas Self-association-structural Studies Ofmentioning

confidence: 99%

Structural and Biophysical Characterization of the Interactions between the Death Domain of Fas Receptor and Calmodulin

Fernandez¹,

Samal²,

Bedwell³

et al. 2013

Journal of Biological Chemistry

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Biophysical and cell-based evidence for differential interactions between the death domains of CD95/Fas and FADD

Cited by 10 publications

References 21 publications

The Fas–FADD death domain complex structure unravels signalling by receptor clustering

The Fas–FADD death domain complex structure unravels signalling by receptor clustering

Structure of the Fas/FADD complex: A conditional death domain complex mediating signaling by receptor clustering

Structural and Biophysical Characterization of the Interactions between the Death Domain of Fas Receptor and Calmodulin

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